Functions of S100 Proteins

Abstract

The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…105 S100A4 is a member of the S100 family of 25 calcium binding proteins that are widely expressed in vertebrates. [106][107][108][109] All S100 proteins have 2 calcium binding EF-hands that cause a conformational change in the protein upon calcium binding, exposing protein binding surfaces and allowing S100 proteins to act as calcium sensors that modulate a range of downstream behaviors through several binding partners. 107,108,110 S100A4 overexpression is associated with metastasis and decreased survival in many cancers, and it is considered an EMT promoter and marker.…”

“…113,115 This is likely because S100A4 interacts with F-actin, non-muscle myosin heavy chain (NMMHC) IIA, tubulin, and non-muscle tropomyosin to increase cell migration through force generation as well as forming and stabilizing lamellipodia. 106,108,[111][112][113]116 Removal of S100A4 from cells results in increased assembly of non-muscle myosin IIA complexes, while overexpression results in large lamellipodia with a loss of focal adhesion maturation and filopodia. 112 S100A4 also interacts with Rhotekin, a Rho binding and regulating protein that participates in actin-based contractility during migration and invasion.…”

“…113,117 S100A4 is upregulated by canonical Wnt signaling, and inhibition of b-catenin decreases tumor cell migration and invasion through downregulation of S100A4. 106,109 NFAT is expressed in metastatic breast cancer and also transcriptionally activates S100A4, 118 Interestingly, NFAT activation is driven by calcium influxes during epithelial scattering of MDCK cells, 31 indicating that there might be multiple connections between S100A4 and increased intracellular calcium concentration in EMT.…”

Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells

“…Among natural targets of extracellular S100A4, RAGE and its downstream signalling pathways gained significant importance and, consequently, forms the link between those recent findings mentioned above 9. In colorectal cancer, S100A4 causes increased cell motility, which is mediated via the receptor for advanced glycation endproducts (RAGE) and downstream (mitogen‐activated protein kinase) (MAPK/ERK) signalling 10.…”

Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation

“…Белки S100 могут формировать как гомо-, так и гетеродимеры; поми-мо Ca 2+ , связывать также Zn 2+ и Сu 2+ . Захват ионов меня-ет пространственную организацию S100 и обеспечивает возможность связи с различными белками-мишенями их биологического действия (документировано более 90 по-тенциальных белков-мишеней) [45].…”